Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy

The Journal of Pediatrics VOL. 55

NOVEMBER,

No. 5

1959

SYMPTOMATIC NEONATAL HYPOGLYCEMIA ASSOCIATED WITH TOXEMIA OF PREGNANCY MARVIN CORNBLATH,

M.D.,* GERARD B.

EPHRAIM

Y.

0DELL,

M.D.,

AND

LEVIN, M.D.

BALTIMORE, MD.

U R I N G the first hours a f t e r birth, fasting normal newborn infants develop blood s u g a r levels which are considerably lower t h a n those of fasting older children or adults2, 2 I n p r e m a t u r e infants 3 and in the offspring o f diabetic mothers, ~-7 this hyp o g l y c e m i a is even m o r e m a r k e d . Y e t it is so unusual in the n e w b o r n to find clinical signs clearly a t t r i b u t a b l e to h y p o g l y c e m i a t h a t these low levels are often r e f e r r e d to as physiologic, s This r e p o r t describes 8 cases of spontaneous h y p o g l y c e m i a with s y m p t o m s beginning on the second or t h i r d d a y of life in infants born to mothers with toxemia. They differ from previously reported cases s-~2 by tl%ir self-limited

D

COUFSe. P A T I E N T ~ i A T E R I A L AND ~ I E T H O D S

Of the 5 patients observed by the authors, 4 (B. M., D. B., P. B.,I and F. Z.) were born at The Johns Hopkins J~rom t h e H a r r i e t L a n e H o m e of T h e J o h n s H o p k i n s H o s p i t a l , a n d t h e D e p a r t m e n t s of P e d i a t r i c s of S i n a i H o s p i t a l a n d T h e J o h n s H o p k i n s U n i v e r s i t y School of Medicine. This investigation w a s supported by res e a r c h g r a n t s f r o m t h e l'r I n s t i t u t e of Arthritis and Metabolic Diseases, National I n s t i t u t e s of H e a l t h , P u b l i c H e a l t h S e r v i c e , a n d t h e N a t i o n a l I n s t i t u t e of N e u r o l o g i c Diseases and Blindness. * A d d r e s s , M i c h a e l R e e s e H o s p i t a l , 29th S t r e e t a n d E l l i s A v e . , C h i c a g o 16, ill. t~u w i s h to t h a n k Dr. H e n r y Seidel f o r p e r m i s s i o n to r e p o r t his p r i v a t e e a s e P. ~ . 545

Hospital 1 and one (G. A.) at Baltimore City HospitalY* The histories of two additional patients (R. F.3t and B. D.) were obtained f r o m the H a r r i e t Lane medical records and of another (R. T.) f r o m the records of the Baltimore City I-Iospital. M a n y of the blood sugar determinations are reported as total reducing substance (TRS). The others represent true blood sugar and were determined b y the method of Somogyi-Nelson. 13 The chemical determinations on the patients at the Baltimore City Hospital were p e r f o r m e d in the Pediatric Chemistry Laboratory, those at Johns Hgpkins in the central hospital laboratory. Tolerance tests were done on the first 3 infa'nts (B. M., D. B., an(] P . B . ) . Glucagon4$ (30 mcg. p e r kilogram) was given intravenously and capillary blood sugar determinations obtained at half-hour intervals for 2 hours. E p i n e p h r i n e (0.03 ml. per kilogram of epinephrine hydrochloride ] :1,000) was given intramuscularly. Casein tolerance tests were done by * W e w i s h to t h a n k l ) r s . H a r o l d I-t. H a r r i s o n a n d L a w r e n c e :Finberg f o r p e r m i s s i o n to p u b l i s h t h e c a s e s f r o m t h e B a l t i m o r e City Hospital. t T h e c a s e of R. F. h a s p r e v i o u s l y b e e n r e p o r t e d b y Dr. L a w s o n W i l k i n s . 30 S G l u e a g o n w a s s u p p l i e d b y Dr. E. ]={. I < i r t l e y of Eli L i l l y a n d C o m p a n y .

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minuria. On restricted activity and a low salt regime, a weight loss of 6 pounds occurred in one week. L a b o r began spontaneously 2 days later. The blood pressure during labor remained 130/94. Demerol and scopolamine were given 3 hours prior to delivery. L a b o r was uneventful, lasting 102%o hours (the second stage was 5%o hours). The infant was delivered by the vertex in oecipitoanterior position, with elective low forceps over a median episiotomy u n d e r nitrous oxide and oxygen anesthesia. The mother required repair of a fourth-degree laceration. The p o s t p a r t u m course was uneventful and her blood pressure was 104/70 on discharge. The placenta weighed 380 grams and had an adherent clot over ~ of the m a t e r n a l surface. The infant breathed at birth, cried in 40 seconds, and was described as in fair condition. Slight pallor and cya-

administering Casec (calcium caseinate), 1.5 Gm. per kilogram orally, and following the capillary sugar levels before and one-fourth, one-half, 1 and 2 hours after ingestion. Leucine (0.15 Gm. per kilogram) was given orally to one infant (D. B.) and blood sugar determinations followed for 2 hours. CASE REPORTS

The first 2 cases are described in detail and their course illustrated in Figs. ] and 2. The pertinent data on all of the i n f a n t s have been summarized in Tables I and II. The remaining 6 case reports are in the appendix. CASE ] . - - B . M . ( H L H No. B-43258) (Fig. 1), a 2,580 g r a m white male infant, was born on Aug. 5, 1957, 24 days p r i o r to the expected date of confineBirth 4 4

AGE IN HOURS 52 56 60 64

48

PEDIATRICS

~

68

= I00" a~ E =" 8 0 . E

(

7 2 ) 4f

AGEIN DAYS

5 46

B

IO

I2

14

i 6 ~/ 3 2

I

60CD

,I, Ill

o~ 4.0.

8

, I

20.

/?.E Cyonosis

~ Pollor

N

+_ +_

>

+0+

N

N

>

(N =Normal)

44

+

Apneo

J Limpness o Tremors

++

Moro Misc.

4-~ .If +

Z convulsions

=E Glucose

N

+++

--

+ No cry No suck

4-

Moribund Oral [ ]

Lv.

W

:!:!:~r

Milk I--

CLINICAL COURSE IN PATIENT B.a. (CASE I) F i g . 1.

ment. His mother was 20 years old, Rh positive, p a r a 0010, with a negative serologic test for syphilis, and in good health. A t 34 weeks' gestation, she was hospitalized because of a 34 pound weight gain, blood pressure of ]38/94, edema of the hands, and I plus albu-

nosis were noted. Physical examination at 45 minutes of age was unremarkable. At 12 hours of life, routine glucose feedings were offered and taken well, as were the subseqnent evaporated milk with 5 per cent carboh y d r a t e feedings.

CORINBLATI[t ET AL. :

SYMPTOMATIC I~EONATAL HYPOGLYCEMIA

A t 47 hours of age, the i n f a n t was observed to be limp, flaccid, cyanotic, and without Rroro reflex. While he was being examined, the eyanosis gradually diminished. A glucose water feeding was attempted. Limpness and cyanosis increased and sucking reflex was absent. Jaundice was noted. The liver was palpable 1 cm. below the costal m a r g i n and the fontanel was tense. Bilateral snbdural and ventricular taps were negative. D u r i n g a venipuncture, the i n f a n t made jerking movements of all extremities. Blood chemistry determinations revealed the blood sugar to be 20 rag. p e r cent ( T R S ) , nonprotein nitrogen 51 rag. per cent, calcium 9.3 rag. per cent, and bilirubin 16 nag. per cent. The blood type was O, Rh positive, direct Coombs test negative. The i n f a n t improved in color and tone. However, at 55 hours of age he again became cyanotic, hypopneic, jittery, and a p p e a r e d moribund. T w e n t y cubic centimeters of 10 per cent glucose was given r a p i d l y intravenously, followed b y 55 c.c. by intravenous drip. The b a b y responded r a p i d l y within a few minutes, lost all traces of cyanosis, and became less jittery. A lumbar p u n c t u r e was performed at 63 hours of age with the glucose infusion running. The cerebrospina] fluid s u g a r was 45 rag. per cent. A blood sugar determination obtained at about 64 hours of age with 10 per cent glucose r u n n i n g intravenously at the rate of 10 c.c. per hour was 20 rag. per cent ( T R S ) . On the fourth day of life, the intravenous glucose infusion was tempor a r i l y discontinued. A f t e r 6 hours, the b a b y became quite flaccid, acroeyanotic, did not cry or suck, and the Moro reflex was poor. T w e n t y minutes a f t e r the glucose infusion was restarted, the i n f a n t looked better and began to take feedings. The bilirubin was 14.0 nag. per cent and the blood s u g a r 40 rag. per cent ( T R S ) with the infusion running. On the fifth day, the infant was weaned f r o m the infusion and maintained on frequent small feedings of evaporated milk 2:3 with water and 10 per cent added carbohydrate.

5~7

On day 6, a f t e r a 9 hour fast, the blood s u g a r was 14 mg. per cent with no a p p a r e n t clinical signs of hypoglycemia. An intravenous glucose tolerance test was p e r f o r m e d with 25 e.c. of 10 per cent glucose. The highest blood sugar was 64 rag. p e r cent at 1 hour. This had fallen to 40 rag. per cent at 2 hours, at which time 250 meg. of glueagon was given intravenously. I n 30 nainutes, the s u g a r was 50 nag. per cent, falling to 14 rag. p e r cent by the end of 2 hours. A t no time during these procedures did the b a b y show a n y abnormal signs. Thereafter, the baby did well on the frequent feedings. The blood sugar ranged around 60 nag. per cent ( T R S ) 2 to 3 hours a f t e r feedings. On day 7, the nonprotein nitrogen was 60 rag. per cent, bilirubin 5.4 rag. per cent, phosphorus 8.6 nag. per cent, t o t a l protein 4.5 Gna. per cent, and albumin/globulin ratio 2.8/1.7. On d a y 9, a glueagon tolerance test was p e r f o r m e d after a 9 hour fast. The f a s t i n g sugar was 20 rag. per cent, 54 rag. per cent at 30 minutes, and 25 nag. per cent at 90 minutes. Epinephrine (0.08 e.e.) 1:1,000 given intramuscularly 2 hours a f t e r the glueagon produced no hyperglycemic response (Fig. 3). On day 16, a casein tolerance test was perfornaed a f t e r a 9 hour fast. The initial blood sugar was 30 nag. per cent. The patient ingested 1.5 Gin. per kilogram of calcimn caseinate. The blood s u g a r was 31 rag. per cent at 15 minutes, 24 rag. per cent at 30 minutes, and 7 rag. per cent at 120 minutes (Fig. 3). There were no symptoms. The i n f a n t fed well, gained weight, and became more alert. At age 3 weeks he a p p e a r e d normal to examination and weighed 2,750 grams. The blood s u g a r remained in the range of 60 to 90 rag. per cent ( T R S ) 4 hours a f t e r feedings. He was d~scharged home on a 4 hour feeding schedule of an evaporated milk fornaula containing 10 per cent added carbohydrate. D u r i n g the infant's stay in the hospital, additional laboratory examinations were done. Cultures of the blood,

548

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ventrieular, subdural, and spinal fluids were negative. X-rays of the skull and chest were normal. Repeated urinalyses were unremarkable, with no glucosuria or acetonuria. Serum electrolytes were also normal. Subsequent studies included another casein tolerance test at 32 days of age. After a 9 hour fast, the initial sugar was 44 rag. per cent. He ingested 1.5 Gin. per kilogram of calcium caseinate. Blood sugar levels at 60, 90, and 120 minutes were 44, 75, and 44 rag. per cent (Fig. 3). Subsequent fasting blood sugar levels were 80, 92, and 74 rag. per cent at 2 ~ , 5 and 7 months of age, respectively. The patient had grown and developed normally during this time.

of a blood pressure of 170/112, 30 pound weight gain, generalized edema, and frontal headache. She was given 55 Gin. of magnesium sulfate intramuscularly over a 3 day period. Reserpine was given thereafter. On a low salt diet and bed rest, she lost 9 pounds and the blood pressure was 150/105 at discharge. Eleven days later, she was readmitted for epigastric pain and vomiting. The blood pressure was 126/84, urine negative. On bed rest, she improved slowly and one week later, a medical induction of labor was attempted by stripping the membranes. Two days later active labor began. The blood pressure rose to 169/110 and she was given 5 Gin. of magnesium sulfate intrarauscular]y. Labor lasted 57~o hours with a second stage of 3~o hours. The raembranes ruptured spontaneously 3~ hour

CASE 2.--D. B. ( H L t I No. B-43864) (Fig. 2), a 2,140 gram Negro male, was born on Aug. 26, 1957, 25 days

I00"

PEDIATRICS

AGE IN DAYS

AGE IN HOURS F Birth 2 4 ~ 4 4 48 52 56 60 6 4 68 72~ J !

f %

80.

& ,~

60.

m

40.

~

ZO 0

N

RE.

Cyonosis Po//or Apneo Limpness Tremors Convulsions Moro Misc. Glucose Milk

N

N ----~

N

,1

~,, (N :Normal)

4 +

+

+_

+

-I

-14-

No sucl

No .Suck

Poor suck

Oral I.V. E:!:;:!:~:~:~:~:~:?:~:;:~:;:~:;:;:i~

AGTH ~!i:i:i~i:i:i:~:i:~:~:~:~:!:~:~:i:~:~:!:!:!:!:!:~:~:!:i:~ Cortisone ~

Steroid

C L I N I C A l - C O U R S E IN P A T I E N T D.B. ( C A S E 2 ) Fig.

prior to the expected date of confinement. The raother was a 19-year-old Rh positive primipara, with a negative serologic test for syphilis, first seen at 27 weeks' gestation. She was hospitalized for 3 weeks at this time because

2.

prior to delivery. The placenta weighed 470 grs and had many small infarcts on the maternal and fetal surfaces. The blood pressure immediately post partum was 130/95 and at 6 weeks 110/70.

C O R N B L A T H :ET AL. :

S Y M P T O M A T I C :NEONATAL H Y P O G L Y C E M I A

The infant was born spontaneously in vertex presentation. IIe breathed and cried in 10 seconds. Itis immediate condition was "excellent" and physical examinations at birth and at 7 hours of life were normal. Because of his prematurity, the baby was given nothing by mouth for 24 hours and then begun on glucose water. His body temperature remained low and he was put into a Gordon-Armstrong Incubator at 25 hours of age. lie did well until 44 hours of age at which time he fed poorly, was cyanotic when sucking, and had poor muscle tone. At 52 hours of age, the baby was found apneie and pulse]ess, but was resuscitated by manual stimulation. At 56 hours of age there was a recurrence of the apnea with severe bradycardia, and a weak heartbeat. His cry was high pitched and tremors of the right arm were noted. The apnea responded well to epinephrine and caffeine-sodium benzoate, parentermly. Blood obtained at this time showed a sugar level of 24 rag. per cent ( T R S ) , nonprotein nitrogen 44 rag. per cent, calcium 8.7 rag. per cent, phosphorus 8 rag. per cent, sodium and potassium normal. L u m b a r puncture was unremarkable except for a cerebrospinal fluid sugar of 15 rag. per cent. Subdural taps yielded no fluid. At 61 hours the blood sugar was 24 rag. per cent, and the infant was given 100 meg. of glueagon intravenously. The blood sugar was 5 rag. per cent at 63 hours of age (Fig. 3). Physical examination at this time revealed the infant to be alert, active, a n d crying vigorously. One hour later, however, the baby was again cyanotic,' limp, with an apical pulse of less than 40 t~er minute, and no visible respirations. Vigorous physical stimulation initiated only isolated gasping movements. H e responded this time only after endotracheal intubation and mouth-to-tube resuscitation, and intramuscular epinephrine. The blood sugar level was 18 mg. per cent. An intravenous inf u s i o n of 10 per cent glucose was started, but the baby began having quadrilateral j e r k i n g movements. These were temporarily controlled with

549

5 c.c. of 50 per cent glucose and phenobarbital. He was hyperreaetive to stimuli. At the age of 72 hours, the infusion infiltrated and the infant had a generalized elonic seizure which responded to 10 per cent glucose intravenously a n d phenobarbital intramuscularly. Throughout the fourth day of life he did well and the infusion was discontinued. About 2 hours later he became apneic, limp, and unresponsive. The blood sugar level (TRS) was 14 rag. per cent. He responded p r o m p t l y to 10 e.c. of 50 per cent glucose with a return of muscle tone and response to stimuli. The infant was subsequently maintained on an infusion of 10 per cent glucose with added electrolytes, and feedings of I5 per cent glucose by intragastric tube. O n the fifth day of life the infant was still quite lethargic, with blood sugar levels ranging from 10 to 33 rag. per cent (TRS) despite temporary rises to 60 rag. per cent following glucagon and epinephrine (Fig. 3). He was unresponsive, dusky, and ]imp. Because he seemed to be suffering an intractable hypoglycemia, 50 mg. of Solu-Cortef was given intravenously and 20 units of A C T I I intramuscularly. His clinical response was remarkable with restoration of skin color and muscle tone. T h e r e a f t e r 2 to 4 hour fasting Mood sugar levels were 60 to 100 rag. per cent ( T R S ) . On the sixth day of life the intragastric tube was removed and nipple feedings of evaporated milk and water 2:3 with 5 per cent added carbohydrate begun. Thereafter the infant did well. Cortisone was tapered and discontinued by the eighth day of life, and A C T H by the sixteenth. Blood sugar levels after 4 to 8 hour fasts were 64 to 120 rag. per cent dur~ ing this time. Numerous urine examL nations were normal, as were blood chemistry determinations. A casein test meal on the twenty-fourth day of life did not affect the blood sugar (Fig. 3). On the twenty-fifth day of life he was discharged weighing 2,220 grams. A leucine tolerance test was normal at

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THE JOURNAL OF PEDIATRICS

33 days of age (Fig. 3). Fasting blood sugar levels at 3, 10, and 11 months were 62 to 76 rag. per cent. A t 11 months he had grown and developed normally.

Clinica~ Summar~ of the 8' Cases.As noted in Table I all of the mothers had mild pre-eclampsia, consisting of hypertension in all, albuminuria in 4, and excessive weight gain in 2. The medications used in the treatment of the pre-ec]ampsia are detailed in the case reports and were not uniform. TABLE I.

CASE SEX B.M. M

All the infants did fairly well until the onset of symptoms at 40 to 57 hours of age (Table II). Initial symptoms were listlessness and refusal of feedings after milk had been taken well. Apnea and loss of muscle tone followed and after a variable period of time, cyanosis, tremors, and convulsions ensued. Blood sugar levels at the time of convulsions ranged from 1.0 to 24 rag. per cent. In 5 infants the spinal fluid sugar ranged from 0 to 15 rag. per cent and, in several, first

SU~MAI~YOF 8 CASES OF Su NEONATAL I{YPOGLYCEMIA~AxSSOCIATEDWITH TOXEIV[I2~ OF PREGNANCY EACEII GESTATION (WEEKS)

MOTHEK'SPRENATAL COUI~SE

W

361/o

Severe weight gain Mild hypertension

CO~r

OF LAB01~BIRTH WEIGHT AND DELIVERY (GRAMS) Adherent clot over one2,580 third of placenta

D.B.

IV[

C

36~/~

Severe pre-eclampsia

Induction o~ labor Precipitate delivery

2~140

P.B.

M

W

37

Moderate hypertension Albumiuuria

Uterine inertia with intrapartum hemorrhage. Cesarean section

2,310

@. A.

!~

C

38

Hypertension A]buminuria

Prolonged ruptured merebranes Breech presentation

1,360

F.Z.

M

W

39

:Excessive weight gain tIypertension

Precipitate delivery

2,095

R.F.

F

W

37?

"Slight" hypertension

No~te

1,500 3,090 1,812

lZ. T.

M

C

38

Hypertension Albuminuria

Prolonged second stage

B.D.

M

W

32

Hypertension Albuminuria

Nolle

Additional complications in the individual pregnancies included an adherent placental clot (B. M.), induction of labor and precipitate delivery (D. B.), uterine inertia, intrapartum hemorrhage, cesarean section, and multiple birth (P. B.), breech extraction and prolonged ruptured membranes (G. A.), precipitate delivery (F. Z.), and a prolonged second stage of labor (R. T.). Two (R. F. and B. D.) had i1o known complications of labor or delivery. Seven infants were delivered vaginally, one by cesarean section. All but 2 were premature by weight although in 7 eases the length of gestation was 3 6 ~ weeks or more.

suggested the diagnosis of hypoglycemia as a cause for symptoms. Administration of parenteral glucose alleviated symptoms immediately in every infant and was necessary for prolonged periods of time to maintain normal blood sugar levels. Despite these measures, 5 infants had occasional low blood sugar, without symptoms, for varying periods of time. In 5 (B. M., D. B., P. B., R. F., and B. D.) the course was self-]ilnited and benign although one (D. B.) required ACTH and cortisone to control the hypoglycemia. These 5 were developing normally at last examination. Two other infants (G. A. and R. T.) are

COICNBLATH E T A L . :

SYMPTOMATIC

spastic and mentally retarded, and one other (F. Z.) died at 17 days of life Of generalized Pseudomonas sepsis and early toxoplasmosis.

Results of Tolerance Tests.--Various tolerance tests were performed in an attempt to elucidate the etiology of the hypoglycemia observed. These included the administration of glucagon or epinephrine as a test for available hepatic glycogen and of casein or ]eucine as a test for hypoglycemia precipitated by amino acidsf*

NEONATAL

32 days

16days

2L

a% t

....

t

Glucagon Epinephrine

D.B, Case~ AGE 2 days

~8oi

!,oi tGlucagon

551

gestion of Casec resulted in a marked hypoglycemia (Fig. 3). B y the thirtysecond day of life, however, the casein tolerance test was normal. The significance of the apparent transient sensitivity to casein is difficult to i n t e r p r e t since no tests on normal infants are available for comparison. In D. B. (Case 2), glueagon administered at the time of symptoms had no effect oi1 the blood sugar, which continued to fall to v e r y low levels (Fig. 3). A similar failure to respond

"B.M CaseI AGE 9 days

~2ot

IIYPOGLYCEM.[A

Case/>7

5 days

-"

-

t

Casein

24 days

33 days

tEpinephrine tCasein

tLeuc/ne

/

P 8 CaseTn AGE 3days 80] IN Glucose running

M.B,(Frafernoltwin of 5 days N PO.- 9hrs,

?~

~ / ~

~~

Case'iK)

IJItl I hour

tGlucogon

alecogon

EFFECT OF VARIOUS SUBSTANCES ON BLOOD SUGAR 1~ig. 3.

In the first patient, B. M., the intravenous glueagon tolerance test on the ninth day was normal (Fig. 3). Epinephrine following glueagon had no hyperglyeemic effect, suggesting a limited quantity of available glycogen in tile liver. On day 16, the oral in-

to glueagon has been observed during the immediately postnatal rapid fM1 in blood sugar in infants of diabetic mothers. 15 B y the fifth day of life, epinephrine resulted in a good hyperglycemic response (Fig'. 3). Casee on the twenty-fourth day of life had no

(HOURS)

CONDITION

AT BIRTH

Fair Good

F a i r to poor Good

Fair

Good Good

Good

CASE

B.M. D.B.

P.B.

G.A.

F.Z.

R.F. R.T.

B.D.

*Total reducing substance.

40

48-72 46

44

40-48

57

47 44-52

AGE AT ONSET OF SIGNS

x

x

x

x

x x

NOSIS x x

NESS

LIMe-

x x

TREMOR

CONVUL-

x x

x

x

x

x

x x

x

x

x

x x

0

2

0

12

15

CSV

OUTCOME

Well at last follow-up at 5 months Severely retarded, spastic with myoclonie seizures. Institutionalized at 3 years W e l l a t d i s c h a r g e 44 d a y s old

24-18"

sepsis a n d toxoplasmosis

Well at 9 months. Development equal to that of fraternal twin Spastic and jittery at 4 months. Convulsions with normal blood sugar Died at 17 days of Pseudomonas

N o r m a l a t a g e 10 m o n t h s W e l l a t a g e 11 m o n t h s

18" I

2

4

20* 24* 14 1 6*

BLOOD

RETO INTRAVENOUS GLUCOSE

SUGAR CONCENTRA- I~MEDIATE TION AT SYMPTOMS SPONSE

APNEA SIONS (MG. %)(MG. %)

SYiVIPT01~IS AND SIGNS

SUIvKNIAt~YOF THE COUI~SE OF 8 INFANTS W I T H SYMPTOIVIATIC NEONATAL HYPOGLYCEMIA

CYA-

TABLE I I .

C"

O

DO

C O R N B L A T H ET A L . :

SY1KPTOMATIC NEONATAL

appreeiable effect on the blood sugar, whereas leueine on day 33 resulted in a minimal falI in the blood sugar (Fig. 3). The fraternal twins (see Appendix, eases P. B. and 3/[. B.) received glueagon on the t h i r d day of life, a f t e r the symptoms of hypoglycemia had been controlled by parenteral glucose in P . B . Each had a significant and comparable rise in blood sugar suggesting available glycogen in the ]iver. Of interest was the fact that, although P. B. was receiving an infusion of glueose prior to and during the test, his initial blood sugar was 26 rag. per cent, whereas that of his fasting brother (lV[. B.) was 40 rag. per cent. DISCUSSION

Hypoglycemia in the newborn period is rarely associated with cliniea[ signs. IIowever, of 25 eases of chronic idiopathie spontaneous hypoglycemia in infants and children reported by McQuarrie,' 2 became clinically evident during the first day of life and another in the first week. Schwartz and assoeiated ~ described a ease of hypoglycemia which had commenced with convulsions in the thirty-fifth hour of life and had persisted for 17 months at the time of the report. In another ease of manifest hypoglycemia in a neonate, an islet-celladenoma was diseovered at autopsy. = Moreover,

glycogen storage disease of the liver can also be responsible for symptomatic hypoglycemia with convulsions on the third day of life2 ~ In all these eases, the eyano.sis, limpness, jitterihess, apnea, coma, and convulsions which were observed were similar to the symptoms seen in older patients with hypoglycemia. Thus it would appear that while hypoglycemia in the newborn rarely produees diseernible signs, some infants do present clinical manifestations of low levels of circular-

HYPOGLYCEMIA

553

ing glucose. In the 8 cases reported here, convulsions, apnea, tremor, and limpness were associated with a marked hypoglycemia on the second or third day of life and the clinical syndrome was alleviated immediately b y the administration of parenteral glucose. It is noteworthy that 5 of the infants subsequent to treatment had very low blood sugar levels unassociated with a p p a r e n t symptoms or signs. Whether this reflects a clinical tolerance to hypoglycemia or additional factors affecting the response of the central nervous system to low glucose levels is ~mcertain. The initial, response of all of the infants to parenteral glucose is evidence that the hypoglycemia observed was responsible for the symptoms and signs. The unusual features in the eases reported are the self-limited, but quite refractory, course, the fact that 6 of the 8 infants were premature by weight, and the association with pre-eelampsia in the mother. A relatively shmrt, self-limited course is not common with any of the known forms of symptomatic hypoglycemia outlined by Conn and Seltzer. ~6 Organic causes such as hyperinsulinism, hepatic disease, glycogen storage disease, or adrena] or p i t u i t a r y hypofunction seem unlikely to account for such a course. Central nervous system ]esions such as those in G. A. and R. T. may cause hypoglycemia, *~ but these lesions may also be a result of hypoglyeemie attacks. Six infants showed no evidence of cerebral damage. All the infants had been fed prior to the episodes of hypoglycemia, eonsistent with the possibility that a Staub-Traugott phenomenon ~ had led to the symptoms; however, 5 of the infants also had low

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blood sugars when fasting. Idiopathic hypoglycemia as described by McQuarrie 9 is of longer duration, and usually requires long-teria A C T H or cortisone t h e r a p y for maintenance of notmaoglycemia. This measure was required in o{tly 3 of the 8 cases described here and for relatively short periods. Despite being close to term by date, 6 of the infants weighed less than 2,500 grams. In the ease of the fraternal twins (P. B. and M. B.) it was the smaller who had hypoglycemia. The hypoglycemia of the first day of life is greater in prematures than in f u l l 4 e r m infants, especially under stress. 2 Norval 2 followed the blood sugar in 42 p r e m a t u r e infants of whom 9 died. F o u r of the infants who died had blood sugar levels in the range of 4 to 20 rag. per cent. In addition to delayed feedings, other factors which might contribute to a relative hypoglycemia in prematures i n c l u d e inadequate hepatic glycogen stores, inability to mobilize glycogen, ~s and an inefficient regulation of glucose metabolism. These factor's may reflect enzymatic immaturity. The diminished ability of the liver of the p r e m a t u r e infant to conjugate bilirubin ~9 or sulfonamide 2~ and to o~idize tyrosine 2~ are examples of enzymatic immaturity. In animals, glucose-6-phosphatase activity in the liver is markedly di: minished prior to birth. ~2 All of these apparent deficiencies become less evident as the infant matures. The selflimited course of tile hypoglycemia observed in the cases reported is consistent with the theory that an adaptation or maturation of enzymes has occurred. The mothers of all 8 infants in this report had pre-eclampsia. I t is known t h a t infants delivered of women with

OF P E D I A T R I C S

toxemia of pregnancy have an increased morbidity and mortality, 23-2r especially if there is an associated cornplication of labor or delivery. In addition, p r e m a t u r e delivery frequently occurs in toxemie pregnancies, p a r t l y because of complications such as placental hemorrhage and p r e m a t u r e rupture of the membranes and p a r t l y because of early inductions as an obstetric measure to protect the health of the mother. P r e m a t u r e infants born to toxemic mothers have a lower mortality rate than other prematures during tile first day of life, but a higher mortality rate over the first weekY s They are more often edematons, feed poorly, and gain weight more slowlyY ~ Their blood urea nitrogen is higher. 3~ Neonatal cyanotic attacks are frequently associated with pre-eclampsia in the mother. 31 The increase in morbidity may be p a r t l y associated with the administration of drugs such as barbiturates, morphine, and the hexamethonium compounds ~2 to the mother, but for the most part its cause is unknown. This report of 8 cases of symptomatic neonatal hypoglycemia, in all of which the mothers had suffered some manifestations of pre-ec]ampsia, suggests the possibility that some of this morbidity may be due to unrecognized attacks of hypoglycemia. The need for more careful observation of these infants in tile nursery is apparent, aa W h y pre-eclampsia in the mother, often together with some other complication of labor and delivery and low birth weight, should be associated with symptomatic hypoglycemia on the second day of life is obscure. AbnormM diabetic-type glucose tolerance curves have been observed in toxemie mothers 34 but the small birth weights of these infants make it unlikely that

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AL. :

SYIC[PTOMATIC

they are offspring of prediabetie mothers. W h a t effect the pre-eelampsia might have on glycogen stores or glucose metabolism in the fetus and neonate is unknown. W h e t h e r or not more subtle difficulties such as reading disabilities, cerebral palsy, and behavior disorders, all" observed in increased incidence in products of toxemie pregnancies, ~, 3~ are related to hypoglycemia, deserves f u r t h e r investigation. Finally, much has been written to imply that low blood sugar levels in the newbot~a are not of clinical signifieanee.3~, 3s Since hypoglycemia can be responsible for apnea, eyanosis, limpness, and convulsions in the neonate, it should be considered in the differentim diagnosis of these signs in the offspring of toxemie women. SUMMARY

1. Eight cases of symptomatic hypoglycemia with apnea, eyanosis, coma, and convulsions have been described which occurred in infants of 2 days of age delivered of mothers with preeelampsia. 2. Recovery front hypoglycemia took place once the blood sugar levels were exogenously supported. 3. Five infants had no apparent sequelae; 2 infants have permanent central netwous system damage; and one died at 17 days.

4. The implications of these findings in relation to the increased morbidity and mot~cality in offspring of toxemic mothers have been discussed. APPENDIX

Case Reports.-P. B. (JI-II-I No. 61 8650), a 2,310 gram white male infant, was the second-bora of fraternal twins on Nov. 21,

NEONATAL

IIYPOGLYCFMIA

555

1957, 21 days prior to tile expected date of confinement. The mother, a 23-year-old, Rh-positive primipara, with a negative serologic test for syphilis, was followed by her private obstetrician from the ninth week of gestation. The entire prenatal course was uneventful with blood pressure readings of 120-140/70-80. A t 37 weeks' gestation, she was admitted in aetive labor with spontaneously r u p t u r e d membranes of 6 hours' duration. On admission, her blood pressure was 160/106 and narrowing of the retina[ vessels was noted. No edema or albuminuria was present. Labor progressed poorly. She received, intramuscularly, magnesium sulfate (a total of 15 Gin. over 6 hours) and Demerol. A f t e r 17 hours of labor, Pitocin was given intravenously over a 2U~ hour period with poor results. Because of i n t r a p a r t u m bleeding' and uterine inertia, an emergency cesarean section was performed under local anesthesia. The ;placenta weighed 855 g,'ams and was normal. This infant was the second-born of f r a t e r n a l twin boys delivered several minutes after his sibling. IIe cried at birth, but respirations were inadequate for 3 minutes. His initial condition was described as " p o o r " with eyanosis and poo.r muscle tone. A Grade 1 systolic m u r m u r was noted. The infant was placed in an Isolette incubator, with full. humidity and oxygen (35 per cent) and was given penieilli,~ and streptomycin. At 24 hours of age he was sta,'ted on routine breast feedings, along with supplements of 5 per cent glueose and water, t i e nursed fairly well. During the second day of life he sucked poorly. At about 57 hours of age, while at the breast, he began having forceful gasping respirations, and became cyanotic. He responded to oxygen, suction, and parenteral caffeine-sodium benzoate, and became active and alert. Six hours later a generalized seizure occurred, consisting of rhythmic contractions of all four extremities, lasting 11~ minutes, followed by opisthotonus, with facial contractions and apnea lasting

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30 seconds and urination. A f t e r the seizure he was hyperreactive and had an exaggerated More reflex. A l u m b a r p u n c t u r e yielded xanthochromic fluid with 82 red blood cells and 2 round cells p e r cubic millimeter. The cerebrospinal fluid s u g a r was 12 rag. per cent, protein 100 rag. p e r cent, and P a n d y reaction 3 plus. A white blood cell count was 2,300. Blood and cerebrospinal fluid cultures were negative. A t 66 hours of age the blood sugar was 6 rag. per cent (TRS) and the serum calcium 12.7 rag. per cent. A f t e r several cubic centimeters of 50 per cent glucose were given by gastric tube, the blood sugar rose to 14 rag. per cent ( T R S ) . An infusion of 10 per cent glucose was started intravenously. A t 72 hours of age the infusion infiltrated and the i n f a n t had a second hypoglyeemic episode, similar to the first. The 10 per cent glucose infusion was started again and quickly abolished the h y p e r a c t i v i t y and jitterihess and restored the baby's color. Blood chemistry determinations at this time were: sugar, 30 rag. p e r cent ( T R S ) , sodium 150, potassium 4.3, chloride 115, and carbon dioxide 30 mEq. p e r liter. A t 80 hours of age, with the infusion running, the blood sugar was 26 rag. p e r cent ( T R S ) . A f t e r glucagon (30 meg. per kilogram) was administered intravenously, the sugar levels were 50 rag. p e r cent (TRS) at one hour and 38 rag. p e r cent (TRS) at 2 hours (Fig. 3). The inf a n t remained in good condition thereafter, with no abnormal physical findings despite blood sngar levels r a n g i n g from 1] to 26 nag. p e r cent ( T R S ) . On the fifth d a y of life the infusion was continued and oral glucose feedings added. Blood chemistry determinations were normal and s u g a r levels ranged f r o m 44 to 76 rag. p e r cent. The infusion of glucose and electrolytes was discontinued on d a y 8 and routine formula feedings instituted on day 9. Blood sugar levels after 2 to 4 hour fasts ranged from 38 to 50 rag. per cent (TRS) on the ninth to the thirteenth d a y of life. On the ninth day a casein tolerance test was indeterminate

OF

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because of an initially low fasting blood sugar level of 9 rag. p e r cent. H e had no symptoms. On the sixteenth d a y of life the inf a n t weighed 2,235 g r a m s and was discharged on an evaporated milk formula. I I e h a d been followed by his private pediatrician. A t 33/2 months of age, a 9 hour fasting blood sugar level was 50 rag. p e r cent. A t 7 months his development was normal, his height and weight were the same as those of his f r a t e r n a l twin. IV[. B. ( J t I t I No. 618650), a 2,660 g r a m white male infant, was the non-

affected fraternal twin brother of P. B. born several minutes earlier. H e breathed and cried immediately. Physical examination was normal except for a Grade 1 systolic m u r m u r . H e was placed in an incubator with h u m i d i t y and oxygen, and given penicillin and streptomycin. H e was breast fed and received glucose water supplements s t a r t i n g at 24 hours. His course was benign and he never showed a n y signs of jitteriness or convulsions. On the t h i r d d a y of life food was withheld 9 hours p r i o r to a glucagon tolerance test. The fasting s u g a r level was 41 rag. per cent and glucagon (30 meg. per kilogram) was given intravenously. Blood sugar was 66 rag. p e r cent at 30 minutes, 67 rag. per cent at 60 minutes, and 56 rag. per cent a f t e r 2 hours (Fig. 3). A casein tolerance test on the sixth d a y of life was normal. He was discharged on the seventh d a y of life, at a weight of 2,300 grams, taking breast feeding. A t age 3 8 9 months, the blood s u g a r a f t e r an overnight fast was 55 rag. p e r cent. A t 7 months his development was normal. G. A. ( B C I t No. 241033), a 1,360 grant Negro female, was born on March 13, 1958, 10 days p r i o r to the expected date of confinement. The mother was a 30-year-old, Rh-positive, p a r a 2113, with a negative serologic test for syphilis. She was first seen at 18 weeks' gestation and had an uneventful p r e n a t a l course; the blood pressure was 120-140/60-80, Because

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SYMPTOMATIC

of r u p t u r e d membranes she was admitted at 38 weeks' gestation and found to have a blood pressure of 150/100, 4 plus albuminuria, and brisk reflexes. She went into spontaneous labor and received phenobarbital and magnesium sulfate (20 Gin. total intravenously) d u r i n g labor which lasted 7 a ~ o hours. The second stage of labor was 33 minutes. The infant was delivered as an assisted f r a n k breach. The blood pressure was 130/90 3 days a f t e r delivery. The i n f a n t breathed and cried at b i r t h and was in good condition. She was plaeed in an incubator with h m n i d i t y and oxygen a n d was given vitamin K. Ifer condition remained good throughout her first day. At 34 hours of age nipple feedings of glueo,se w a t e r were begun. A t 40 hours of age a shrill cry was noted. A t 48 hours she had a generalized elonie seizure. Physical examination a f t e r w a r d was unremarkable. A l u m b a r p u n c t u r e yielded d e a r , slightly xanthoehromie fluid eontaining no sugar, a protein of 144 rag. per cent, and a chloride of 119 mEq. p e r liter. Blood chemistry determinations at this time were: s u g a r 4=.0 rag. per eent, calcium 8.0 mg. per cent, sodium 131, potassium 6.0, and carbon dioxide 24.3 mEq. p e r liter. The i n f a n t became eyanotie and apneie. The trachea was suetioned u n d e r direct vision and the infant revived b y mouth-to-mouth insufflation. Twenty-five cubic centimeters of 10 per cent glucose were given rapidly intravenously, followed by 3.0 c.e. of 10 per cent calcium glueonate. Within 10 minutes her color was good and she was v e r y active. She was given pheno~ barbital, penicillin, and streptomyein, and a continuous infusion of 10 per cent glucose with added electrolytes. Cortisone, 5 rag. every 6 hours, and A C T H , 4 units every 8 hours, were started at this time. She was digitalized. Throughout the next few hours, the infant remained in good condition. A ehest film was negative. The blood sugar stabilized at 57 to 60 rag. p e r eent.

NEONATAL

HYPOGLYCEMIA

557

Over the next several days the infant was maintained on dilute half-skimmed milk with added carbohydrate, administered by gavage. Sugar levelsremained around 60 mg. per cent. tfowever, because of coffee-ground emesis, the A C T I t was diseontinued on the seventh day of life. She did fairly well and gained slowly. On the fifteenth day of life, site was again noted to have a shrill cry a n d inereased tone, and to be hyperkinetic. Two hours later a blood s u g a r determination was 7 rag. per cent. She was fed and a repeat blood s u g a r was 27 rag. p e r cent, the sodimn 135, chloride 91.5, and potassium 6.2 mEq. p e r liter. TotM serum proteins were 6.3 Gin. p e r eent. A f t e r an intravenous infusion of glucose and water was stained the hypertonie signs graduMly eieared. ACTI.[, 4 to 12 units daily, was reinstituted and maintained for the subsequent 2 months. Blood s u g a r levels obtained at r a n d o m ranged f r o m 37 to 128 rag. per cent. While she was receiving A C T H , glucose occasionally appeared in the urine. H e r course for a time was uneventful. She ate well and gained slowly. On the sixty-third day of life she weighed 2,150 grams. A p r e p r a n d i a l sugar level was 14 rag. p e r cent and a 2 hour postprandial, 1~ rag. p e r cent. F o u r days later blood sugar levels at similar times were 63 and 119 rag. per cent. On the seventy-second d a y of life, while still reeeiving A C T H , the i n f a n t had two successive generalized elonie seizures, each of a few seconds' duration. The eyes deviated to the left, and she drooled saliva. Blood sugar at, this time was 63 rag. per cent. Several times in the next 2 days she had similar seizures. Blood sugar levels obtained before as well as a f t e r some of these seizures were repeatedly 81 to 115 rag. p e r cent. She was started on phenobarbital. The A C T I t was slowly t a p e r e d and was discontinued oa the eighty-first d a y of life. No furthe# seizures occurred after the seventy-third d a y of life b u t she

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remained hyperirritable and spastic. An electroencephalogram was consi'stent with a diagnosis of idiopathic convulsive disorder. F. Z. ( H L H No. B52410), a 2,095 gram white male infant, was born on June 4, 1958, 4 days prior to the expected date of confinement. The mother was a 40-year-old, Rh-positive, p a r a 3104, with a negative serologic test for syphilis. She had had mild hypertension during her previous 3 pregnancies. H e r first prenatal visit, at 28 weeks' gestation, revealed a blood pressure of 140/90, b u t no edema or albuminuria. Serpasil was given orally for the elevated blood pressure with good response. At term, the mother was admitted in active labor with r u p t u r e d membranes of questionable duration. A f t e r 9 hours of labor, the patient went suddenly from a cervical dilatation of 2 era. to completion of the second stage labor in 6 minutes. She received no medication or anesthesia. H e r bIood pressure ranged from 145-160/90-100 during labor and was 1.32/76 at discharge 3 days post partum. The infant was born spontaneously in vertex presentation. A f t e r an initial gasp, he did not breathe or cry for 2 minutes. His immediate condition was "fair." He was placed in a GordonArmstrong Incubator. A t 4 hours of age he was pink and active, with a good cry, suck, and More reflex. Except for occasional hypothermia and jitteriness, he did well for the first 40 hours of life. A t this time he was begun on glucose water feeding's. At the age of 44 hours, while being fed, a generalized tonic-clonie convulsion occurred, associated with breathholding" lasting" 1 5 seconds. Subsequently he was drowsy and restless. There were spontaneous tremors of the arms and legs. When 47 hours old he had a similar apneic convulsive episode, accompanied by marked cyanosis, lasting 30 to 45 seconds. A transient left facial palsy was detected, along with tremors, mainly of the ]eft arm.

Tile blood sugar was 2 rag. per cent and calcimn 11.7 rag. per cent. L u m b a r puncture yielded a very slightly xanthochromic fluid with 2 mg. per cent sugar, a negative P a n d y reaction, and 2 cells per cubic millimeter. The child was given 2 c.c. of 50 per cent dextrose in water intravenously and an infusion of 10 per cent dextrose was begun. Within 5 minutes he was less jittery, breathing deeply, and had better color. Physical examinations were unremarkable, except that no lV[oro reflex could be elicited. The liver was palpable one fingerbreadth below the costal margin. The urine was normal. The third day of life was uneventful. His infusion was continued, and was supplemented with oral feedings of an electrolyte mixture in 10 per c e n t dextrose. Blood chemistry determinations were calcium 10.5 mg. per cent, phosphorus 5.0 rag. per cent, sodium 134, chloride 95.2, and potassium 4.3 mEq. per liter. The bilirubin was 9.6 rag. per cent (direct 3.9 rag. per cent), serum protein 5.6 g. per cent, with albumin 3.2 and globulin 2.4 Gin. per cent. Several random blood sugar determinations ranged from 6 to 173 mg. per cent. He was kept on oral feedings thereafter and showed no more evidence of hypoglycemia, either clinically or chemically. He remained janndieed, however, had diarrhea with greenish stools, and had an itmitated infected rash about the mnbilieus and genitals. He was given chloramphenieol, penieilIin, special feedings, and general supportive care. On the tenth day of life x-rays showed right u p p e r and lower lobe pulmonary infiltrates which remained unchanged on subsequent fihns. The infant became lethargic and poorly responsive; the liver was palpable 2 fingerbreadths below the costal margin. IIis condition deteriorated progressively thereafter, and he died on J u n e 20, 1958, when 17 days old. Autopsy revealed generalized Pseudomonas aeruginosa sepsis with multiple areas of necrosis and mild e a s y toxoplasmosis.

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SYMPTOMATIC

R. F. ( H L t I No. A-63667), a 1,550 g r a m white female child, was born on J u n e 19, 1948, 1 to 3 weeks p r i o r to the expected date of confinement. Resuits of the serologic test for syphilis on the moiher were unknown, but the infant proved to be STS negative. The mother was a 20-year-old p r i m i p a r a . Because of hypertension she had been given a low salt diet during her one visit to a p r e n a t a l clinic. The i n f a n t was born at home spontaneously in vertex presentation with the assistance of a midwife. The i n f a n t breathed and cried immediately. Because of her small size she was brought to the H a r riet Lane H o m e p r e m a t u r e nursery. On admission at age 1 hour she was in excellent condition. The i n f a n t was started on glucose w a t e r the first day of life, and on a dilute half-skimmed milk f o r m u l a with added c a r b o h y d r a t e the second day. On the t h i r d d a y of life the child suddenly developed poor color, i r r e g u l a r respirations, and convulsions. Subdural t a p s yielded no fluid. A lumbar p u n c t u r e was unremarkable, except t h a t no sugar was found in the spinal fluid. The blood s u g a r was 18 rag. per cent ( T R S ) . Two cubic centimeters of 50 p e r cent glucose were given intravenously, with immediate cessation of symptoms. Blood s u g a r at 62 hours was 46 rag. p e r cent ( T R S ) . Repeated doses of intravenous glucose had to be given in order to maintain the sugar level as high as 40 rag. per cent. A t 80 and 104 hours of life the Mood s u g a r was 18 rag. p e r cent ( T R S ) . No symptoms were noted on either occasion. The epinephrine tolerance test showed a normal hyperglycemic response. On one occasion a half-hour p o s t p r a n d i a l s u g a r level was 72 mg. p e r cent ( T R S ) , bnt most of the hMf-hour postprandial s u g a r levels ranged f r o m 32 to 40 rag. per cent ( T R S ) . The nonprotein nitrogen was 46 rag. p e r cent, calcium 9.6 mg. per cent, phosphorus 5.2 rag. p e r cent, sodium 111 and carbon dioxide 26.6 mEq. per liter. No f u r t h e r con-

NEONATAL HYPOGLYCEMIA

559

vulsions occm-red, b u t because of recurrent low blood sugar, adrenal cortical extract administration was begun on the fifth day. A three hour postprandiM blood sugar was again below 20 rag. p e r cent ( T R S ) , and a 2 hourly feeding schedule was utilized, with a dilute half-skiimned milk formula. By the t e n t h d a y the i n f a n t was doing quite we]l and having no f u r t h e r convulsions. She seemed extremely hungry, and was given a high calorie intake. On the nineteenth d a y adrenal cortical extract was discontinued. As the period between feedings was gradually lengthened her blood sugar levels were again as low as 16 to 18 rag. per cent ( T R S ) on several occasions as late as the thiICy-first day of life. Two glucose tolerance tests and an insulin tolerance test were normal. Because of the recurrence of the hypoglycemia, adrenal e o r f e a l extract, administration was reinstituted at about 1 month of age, and maintained again for 10 days. F r o m this time on the blood sugar g r a d u a l l y increased into the notarial range. B y 5 weeks of age she was doing well on 3 hourly feedings, and by 10 weeks on 4 hourly feedings. A t 12 weeks, a f t e r an 8 h o u r fast, the blood sugar was 68 mg. p e r cent ( T R S ) . On the ninety-eighth day, weighing 3,900 grams, the child was discharged. She was seen several times thereafter in the outpatient depa~cment, and when lost to follow-up a f t e r 6 months of age was doing w e l l No f u r t h e r blood sugar determinations were obtained. R. T. ( B C H No. 235175), a 3,090 g r a m Negro male infant, was born oil Feb. 14, 1955, 5 days p N o r to the expected date of confinement. His mother, an Rh-positive, 16-year-old p r i m i p a r a , with a negative serologic test for syphilis, had hypertension (blood pressure 125/100) and 3 plus albuminuria for at least a week pNor to delivery. The total ]ength of labor was 8 5 ~ o hours with a second stage of 1 2 ~ o hours. The i n f a n t was delivered b y elective low foreeps over a

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median episiotomy. The mother received intramuscular magnesium sulfate (10 Gin.) during labor. The postp a r t u m Mood pressure was 120/80 and urine normal. The baby was in good condition at birth. A t 13 hours of age the infant was started on 4 hourly breast feedings. A t the forty-sixth hour of life, he was found cyanotic, apneic, and stiff, with arms and legs shaking. His heart rate was 80 per minute. He was resuscitated with mask oxygen and manual stimulation. Over the next several hours he had repeated episodes of apnea and eyanosis, but always responded when stimulated. There was apparent marked peripheral vasoconstriction. He was kept in a humid incubator with oxygen and given penicillin and streptomycin. When 52 hours old, his blood sugar was found to be 1.0 rag. per cent. F i f t e e n cubic centimeters of 50 per cent glucose was given intravenously with immediate improvement in respirations and an increase in the heart rate from 110 to 150 per minute. The child became more alert and his cyanosis disappeared. A venous cut-down was done, and an infusion of 5 per cent glucose containing 10 rag. hydroeortisone was begun. At this time blood ehemis.try determinations were: sodium 155, potassium 6.5, and chloride 115 mEq. per liter, serum protein 6.0 Gin. per cent, with albmnin/globulin ratio of 3.2/2.8, alkaline phosphatase 3.6 Bodansky units, bilirubin 13.8 rag. per cent (direct 1.4 rag. per cent), carbon dioxide 21 mEq. per liter, ealeitml 10.4 rag. per cent, and blood urea nitrogen 34.6 rag. per cent. The urine was unremarkable. Over the next day the child seemed better, but early on the f o u r t h day of life he had a convulsive seizure, accompanied by eyanosis and v e r y cold extremities. When 50 per cent glucose was pushed into tile infusion he became more active and responsive but remained hypertonie. L a t e r that day he repeatedly vomited, including one emesis of blood-streaked material.

OF

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Serum electrolytes and blood sugar levels with the infusion running were normal. On the seventh day of life the infusion was discontinued, but hydroeortisone was continued through the eleventh day. Oral feedings were begun, t i e remained quite spastic but had no f u r t h e r convulsions. Random blood sugar levels were in the range of 42 to 58 rag. per cent and serum electrolytes were normal. During the second week of life an episode of diarrhea occurred. An abscess on the left leg had to be incised and drained, and he was treated with Terramycin. B y the fourth, week of life feedings were taken well and his weight was 3,230 grams but he was still quite hypertonic. Oil the twenty-fifth day of life he was discharged from the hospital. The patient was seen frequently in the City Hospital pediatric clinic and observed to gain weight. Ite was retarded and spastic, however, and suffered myoelonie seizures. During his first 6 months serum ehemistry determinations were r e p e a t e d l y found to be normal with fasting blood sugar levels ranging from 38 to 50 rag. per cent. A sickle cell p r e p a r a t i o n was negative. Skull films were normal. When 18 months old the baby was still having seizures, was spastic, and could not sit alone. IIe continued to progress poorly and when 3 years old was admitted to a home for r e t a r d e d children. B. D. ( t I L H No. A77855), a 1,812 gram white male child, was born on May 1, 1950, 8 weeks prior to the expected date of confinement. Itis mother, a 24-year-old, Rh-positive primipara, with a negative serologic test for syphilis, had 2-3 plus albuminuria and hypertension (160/90) for a month prior to delivery. Labor lasted 24 hours. The i n f a n t was del i v e r e d by elective low forceps. He breathed spontaneously and was said to be in good condition at birth. The infant did well until 40 hours of age, at which time he spit up his feeding, became stiff, and had elonie

CORNBLATH ET AL. :

SYMPTOMATIC NEONATAL ItYPOGLu

jerks. H e was t r a n s f e r r e d to the I I a r riet L a n e H o m e a t t h i s time. O n arr i v a l at 43 hours of age, he was jittery and mildly ieteric, but alert, with good color, and the physical examination was otherwise normal Lumbar p u n c t u r e r e v e a l e d a n o r m a l eerebrospinal fluid except for a qualitatively low sugar. T h e blood s u g a r was 24 rag. p e r cent ( T R S ) . T h e b a b y was given 5 p e r cent glucose o r a l l y every 4 hours. H e c o n t i n u e d to b e j i t t e r y . A t 63 h o u r s of age, spastic j e r k i n g movem e n t s followed b y cyanosis a n d g a s p i n g respirations occurred. The blood s u g a r was 18 rag. p e r cent ( T R S ) . E i g h t cubic c e n t i m e t e r s of 50 p e r cent glucose was g i v e n i n t r a v e n o u s l y w i t h instantaneous improvement in respirations, color, a n d cry. A t 66 h o u r s of age, the blood s u g a r was 70 rag. p e r cent ( T R S ) a n d c a l c i u m 9.2 rag. p e r cent. T h e i n f a n t was s t a r t e d on 30 c.c. of 10 p e r c e n t glucose b y g a r a g e every 4 h o u r s a n d developed loose stools. Two blood s u g a r levels b e t w e e n 66 a n d 100 h o u r s of age were 72 a n d 62 rag. p e r cent ( T R S ) . Evaporated milk f e e d i n g s were s t a r t e d a n d tolerated well. H e h a d n o f u r t h e r episodes of a p n e a or seizures. A n i n t r a m u s c u l a r e p i n e p h r i n e tolerance test on the e i g h t h d a y of life a n d a n i n t r a v e n o u s test on the t e n t h d a y of life showed n o rise i n blood sugar. T h e f a s t i n g level on the s i x t e e n t h d a y of life was 32 rag. p e r cent ( T ~ S ) . O n d a y 19, a n i n t r a v e n o u s glucose t o l e r a n c e test was n o r m a l . H i s fasti n g s u g a r a t this t i m e was 68 rag. p e r cent ( T R S ) . H e was d i s c h a r g e d on the f o r t y f o u r t h d a y of life w e i g h i n g 2,680 grams. No a b n o ~ n a l i t i e s were n o t e d at this time. REFERENCES 1. IIartmann, A. F., and Jaudon, J. C.: Hypoglycemia, g. PEDIAT. 11: :[, 1937. 2. Norval, IV[. A., Kennedy, R. L. J., and Berkson, J.: Blood Sugar in Newborn Infants, J. PEDIAT. 34: 342, 1949. 3. Norval, :h~. A.: Blood Sugar Values in Premature Infants, J. PEDIAT. 36: 177, 1950.

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4. Miller~ II. C, and Ross, R. A.: Relation of Hypoglycemia to the Symptoms Observed in Infants of ])iabetlc Mothers, J. PEDIA~. t6: 473, 1940. 5. Pennoyer, ~I. 1VL, and IIartmann, A. F.: Management of Infants Born of Diabetic 1Viothers, Postgrad. Med. 18: 199, 1955. 6. Reis, R. A, DeCosta, E. J., and Allweiss, M. ]).: The Management of the Preg nant Diabetic Woman and Her Newborn Infant, Am. Y. Obst. & Gynec. 60: 1023~ 1950. 7. Farquhar, J. W.: The Significance of Itypoglycemia in the Newborn Infant of the Diabetic Woman, Arch. Dis. Chi]d~ hood 31: 203, 1956. 8. Desmond, M. 1VL: Observations Related to Neonatal Hypoglycemia, J. PEDIAT. 43: 253, 1953. 9. McQuarrie, L: Idiopathic Spontaneously Occurring IIypoglycemla in In~ rants, A. M. A. Am. J. Dis. Child. 87: 399, 1954. 10. Mason, If. If., and Andersen, ]). H.: Glycogen Disease, Am. J. ])~s. Child 61: 795, 194L 11. Schwartz~ O., @ildner, ~[. @., Rosenblum, J., and Avin, J.: Neonatal tIypoglycemia, Report of a Case of Unusual Duration, Pediatrics 16: 658~ 1955. 12. Sherman, If.: Islet-Cell Tumor of Pan~ ereas ~n a Xewborn Infant (Nesidioblastoma)~ Am. J. Dis. Child. 74: 58, 1947. 13. Cornblath, M., Levin, E. 5(, and Gor~ don, J-t. If.: Studies of Carbohydrate Metabolism in the Newborn. 1. Capri]ary-Venoas Differences in Blood Sugar in Normal Newborn Infants, Pediatrics 18: 167, 1956. 14. Cochrane, W. A, Payne, W. W., Simpkiss, M. J , and Woolf, L. I.: Familial Hypoglycemia Precipitated by Amino Acids, J. Cl~n. Invest. 35: 411, 1956. 15. Cornb]ath~ lV[.~ l~icolopoulos, ]).~ and Ganzon, A.F.: The Effect of G]ucagon on the Offspring of Diabetic Mothers. In preparation. 16. Conn, J. W., and Seltzer, IVi. ]).: Spon.raucous I-Iypoglycemla, Am. J. 1VIed. 19: 460~ 1955. ]7. ])arrow, D. C.: 1gental Deterioration Associated With Convulsions and Hypoglycemia, Am. J. Dis. Child. 51: 575, 1936. 18. Cornblath, )/I., Levin, E. Y., and 1V[arqnetti, E.: Studies of Carbohydrate Metabolism in the Newborn. 1I. The E f feet of G!ucagon on the Concentration of Sugar in Capillary Blood of the Newborn Infant, Pediatrics 21: 885, 1958. 19. Lathe, G. If., and Walker, hr.: An Eno zyme Defect in Ituman Neonatal Jaun. dice and in Gunn's Strain of Jaundiced Rats, Biochem. J. 67: 9P, 1957.

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20. Fichter, E. J., and Curtis, J. A.: Sulfonamide Administration in iXIewborn and Premature Infants, Pediatrics 18: 50, 1956. 2]. I~retchmer, N., Levine, S. Z., hlcNamara, II., and Barnett, II. L.: Certain Aspects of Tyrosine Metabolism in the Young. 1. The Development of the Tyrosine Oxidizing System in IIuman Liver, J. Clin. Invest. 35: 236, 1956. 22. Nemeth, A.M.: Glucose-6-Phosphatase in the L i v e r of the F e t a l Guinea Pig, J. Biol. Chem. 208: 773, 1954. 23. E a s t m a n , N . J . : P r e m a t u r i t y F r o m the Viewpoint of the Obstetrician, Am. Pract. 1: 343, 1947. 24. Anderson, IN. A., and Lyon, R. A.: Causes of P r e m a t u r i t y . 1. Review of the L i t e r a t u r e , Am. J. Dis. Child. 58: 586, 1939. 25. Engle, E. T., editor: P r e g n a n c y Wastage, Springfield, Ill., 1953, Charles C Thomas. 26. Tay]or, E. S., Phalen, J. R., and Dyer, It. L.: Effect of Obstetric Difficulties and l ~ a t e r n a l Disease on P r e m a t u r e Inf a n t ~[ortality, J. A. IV[. A. 141: 904, 1949. 27. Brown, E. W., Lyon, R. A., and Anderson, N. A.: Causes of P r e m a t u r i t y . VI. Influence of Toxemia on the Incidence of P r e m a t u r j t y , Am. J. Dis. Child. 71: 378~ 1946. 28. Ifallman, IN.~ I~unnas, M., and Paavo, V.: Zur Sterblichkeit und Entwicklung der Kinder vo~ Miittern mlt i)bersta~dener Schwangerschafts-spiittoxiimie, Ann. pedlar. F e n n i a e 1: 148~ 195~-1955. 29. Brash, A. A.: The Effect of Toxemia of P r e g n a n c y Upon the F e t u s and ]Newb o r n Child, Arch. Dis. Childhood 24: 107, 1949.

30. McCance, R. A., and Widdowson, E. M.: P r o t e i n Catabolism and Renal F u n c t i o n in the First 2 Days of Lifo in Premature Infants and IViultiple Births, Arch. Dis. Childhood 30: 405, 1955. 31. lllingworth, R. S.: Cyanotic Attacks in INewborn Infants, Arch. Dis. Childhood 32: 328, 1957. 32. fin]lure, J. L., and IIatchuel, W. L. F.: Congenital Paralytic Ileus in a Premature Baby as a Complication of Ifexamethonium Bromide Therapy for Toxemia of Pregnancy, Arch. Dis. Childhood 29~ 354, 1954. 33. Gordon, If. If.: Some Methods of Improving Pediatric Care of Newborn Infants, New York J. Med. 55: 2648, 1955. 34. Burr, R.L.: Peripheral Utilization of Glucose in Pregnancy. II. Pre-eclampsia, Obst. & Gynec. 6: 51, ]955. 35. Pasamanick, B., and Lilienfeld, A. IV[.: Association of M a t e r n a l and F e t a l Factors W i t h Development of ]Vieutal Deficiency. 1. A b n o r m a l i t i e s in the Pren a t a l and P a r a n a t a l Periods, J. A. IV[. A. 159: 155, 1955. 36. Dearer, G. G.: Etiologic Factors in Cerebral Palsy, Bull. New York Acad. 1V~ed. 28: 532, 1952. 37. I(omrower, G. IV[.: Blood Sugar Levels in Babies Born of Diabetic Mothers, Arch. Dis. Childhood 29: 28, 1954. 38. Pedersen, J.: Diabetes and P r e g n a n c y : Blood Sugar of INewborn I n f a n t s During F a s t i n g a n d Glucose A d m i n i s t r a t i o n , Copenhagen, ]952, Danish Science Press. 39. Wilkins, Lawson: The Diagnosis and T r e a t m e n t of Endocrine Disorders in Childhood and Adolescence, Springfield, Ill., 1957, Charles C Thomas, Publisher, p. 464.